Gene Therapy Passes Important Test, in Monkeys

By NICHOLAS WADE

Published: February 23, 1999

PHILADELPHIA—
A colony of 54 rhesus monkeys at the University of Pennsylvania in Philadelphia was peacefully watching an episode of the second ''Star Trek'' series one recent afternoon when an alien-looking squad of higher primates, decked out in masks and white disposable boiler suits and ridiculous bootees, marched into their quarters.

The invaders politely avoided staring any monkey in the face, a perilous faux pas in simian society, but there was no disguising their intent: to make one of the residents surrender a sample of her blood.

The monkeys are press-ganged pioneers in a bold medical frontier, the treatment of disease by reprogramming the body's genetic instructions. Gene therapy, as it is hopefully known, has long been a field of high promise and low fulfillment. The promise is evident: all diseases, even infections, have a genetic component, and the best possible treatment in many cases would be to repair the genetic defect that permits the disease.

But inserting genes into human cells in full working order has proved to be exasperatingly difficult. More than 230 clinical trials of genetic engineering techniques are now in progress, but most are at a preliminary stage and none has yet led to an approved therapy. Along with a batch of recent experiments at other universities, the Penn monkeys represent one of the few rays of hope in a long series of setbacks. Not only do six of them now carry a newly inserted gene that makes a therapeutic protein, but the gene can be switched on at will simply by giving the monkey a pill.

The monkeys belong to the university's Institute for Human Gene Therapy, directed by a youthful-looking veteran of the gene therapy wars, James M. Wilson. Dr. Wilson has corralled the resources to pursue a broad-based strategy. Not for him the gamble of going after a single disease, with heavy odds of failure. He is pursuing a wide range of maladies with a variety of methods. ''I will allow nothing technical to get in our way,'' he says firmly in a late-evening conversation in his office.

Mouse rooms and monkey colonies, where gene insertion techniques must be tested before being tried in patients, do not come cheap. Dr. Wilson's virus manufacturing center cost $5 million to build. Merely walking into it costs $20 -- the price of the disposable clothes worn to prevent people from contaminating the growing viruses.

Viruses are both the hope and despair of genetic engineers. Viruses can focus in on specific kinds of cells, penetrate their membranes and insert their genes in working order into the cell's DNA. Most approaches to gene therapy use viruses as the vehicle to convey genes to target cells. The virus's harmful genes are stripped out and a therapeutic gene inserted in their place.

In the mid-1980's, when Dr. Wilson joined the field, a disabled mouse virus was everyone's favorite candidate. But the virus infected only cells that were dividing. The next candidate was adenovirus, a cause of the common cold. Adenovirus is a fine vehicle; it inserts new genes into many kinds of human cell, and the genes produce protein. But only for eight weeks or so. That is how long it takes for the body's immune system to identify and root out every Trojan horse cell where an adenovirus, even a disabled one, is lurking.

In 1993, Dr. Wilson left the University of Michigan and a Howard Hughes fellowship -- a munificent but nontransferable kind of research grant -- to move to Penn. The dean of its medical school, Dr. William N. Kelley, made it a crusade to get gene therapy off the ground and persuaded Dr. Wilson, his former Ph.D. student, to head the new institute.

Two years later the whole community of genetic engineers was plunged into a crisis of confidence. The National Institutes of Health, finding that $200 million, some 2 percent of its budget, was going into gene therapy research, commissioned a critical review of the field. The review's authors chided gene therapists for promising too much and delivering too little.

The many exaggerated claims for gene therapy ''threaten confidence in the integrity of the field,'' the institutes' report said.

A shakeout followed, but Dr. Wilson escaped damage. ''Personally it helped us, because it eliminated a lot of the hacks,'' he said. ''So we contrived to grow after that.'' His institute, the largest of its kind, has a staff of 187 people and an annual budget of $25 million, half of which comes from the National Institutes of Health and the rest from industry and foundations.

''It's a very impressive operation and he has been combining a lot of basic science with applications,'' said Dr. Theodore Friedman, a gene therapy expert at the University of California, San Diego.

Dr. Wilson is now working with a new gene delivery system, one based on a small virus called adeno-associated virus. It has only two genes, both of which can be removed, leaving just its head and tail as a shell to carry therapeutic genes into target cells. The little virus does not greatly provoke the body's immune system.